The present invention refers to a process for the conversion of 6xcex2-fluoro derivatives into the corresponding 6xcex1-fluoro derivatives of pregnane compounds of formula (I) reported hereinafter, useful as intermediates for the preparation of anti-inflammatory pharmaceutical formulations.
6xcex1-fluoro substituted isomers of pregnane derivatives exert a pharmacological action, which makes them useful in the preparation of anti-inflammatory pharmaceutical formulations. Conversely, the corresponding 6xcex2-fluoro derivatives do not exert any pharmacological action.
A number of procedures for the preparation of 6-fluoro pregnane derivatives have been developed so far. However, all of them yield mixtures of the two isomers with relatively high 6xcex2/6xcex1 ratios. It follows that, to obtain the pharmacologically active isomer only, isomer 6xcex2 must be converted into isomer 6xcex1.
By way of example, U.S. Pat. No. 2,961,441 discloses a process for the preparation of 6-fluoro substituted pregnane derivatives, which yields isomer 6xcex2. This isomer is then converted into the corresponding isomer 6xcex1 by treatment with an acid or a base, such as HCl or KOH, in an appropriate organic solvent, such as acetic acid, chloroform, methanol or ethanol.
U.S. Pat. No. 3,980,778 describes the preparation of a 6xcex1-fluoro substituted pregnane derivative by fluorination of a suitable substrate. Said reaction yields a 6xcex2/6xcex1 isomeric mixture in which isomer 6xcex2 predominates. According to said patent, the conversion of isomer 6xcex2 into the corresponding isomer 6xcex1 may be carried out e.g. by treatment with HCl or with a dimethylformamide-HCl complex in an inert organic solvent, such as chloroform or chloroform-ethanol mixtures.
Still unresolved is the problem of converting 6xcex2-fluorosteroids into the corresponding pharmacologically active 6xcex1-fluoro derivatives by means of processes not requiring drastic reaction conditions, though maintaining short reaction times. Said drastic conditions would make the process inapplicable to substrates with unstable functional groups, e.g. epoxides, esters or acetals.
It has surprisingly been found that it is possible to obtain a mixture of isomers with a 6xcex1/6xcex2 ratio above 95:5 also starting from pure isomer 6xcex2 or from mixtures in which isomer 6xcex2 predominates, simply by treating the starting mixture in an opportunely selected organic solvent with an organic base containing a diazoimino group.
It is, therefore, an object of the present invention to provide a process for the isomerisation of 6xcex2-fluoro derivatives into the corresponding 6xcex1-fluoro derivatives of pregnane compounds of formula (I), comprising the reaction of 6xcex2-fluorosteroids, or of 6xcex1/6xcex2 isomeric mixtures, with an organic base, to obtain a 6xcex1-enriched 6xcex1/6xcex2 mixture with a 6xcex1/6xcex2 ratio higher than 95:5 
where R is H or an acyl group containing 1 to 5 carbon atoms in the alkyl chain; Rxe2x80x2 is OH or an acyloxy group containing 1 to 5 carbon atoms in the alkyl chain; Rxe2x80x3 is H or a methyl group; or Rxe2x80x2 e Rxe2x80x3, taken together, form a 
group, in which A and B, identical or different from each other, are H or an alkyl group containing 1 to 4 carbon atoms; X is H, Y is OH or a carbonyl group; or X and Y, taken together, are an epoxy group,
and where a double bond may be present between positions 1 and 2. said isomerisation process being characterised by the fact that the organic base contains a diazoimino group and the reaction is carried out in an aprotic polar organic solvent.
The present process allows the obtainment of 6-fluoro substituted pregnane derivatives of formula (I) in the form of 6xcex1-enriched isomeric mixtures with a 6xcex1/6xcex2 ratio higher than 95:5, through a simple basic isomerisation that yields the final product starting from pure isomer 6xcex2 or from mixtures with any 6xcex1/6xcex2 ratio. In the process according to the present invention preferred are the pregnane derivatives of formula (I) above reported wherein X and Y, taken together, are an epoxy group.
The 6xcex1/6xcex2 ratio of the final product was determined by NMR analysis and was found to be higher than 95:5.
Compared with the processes of the prior art, the reaction of the present invention is surprisingly advantageous because, under mild reaction conditions and within much shorter reaction times, it gives high-purity 6xcex1-fluorosteroids of formula (I) in high yields.
According to the present invention, the starting compound is caused to react with an organic base containing a diazoimino group, selected e.g. from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5)(DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and 1,1,3,3-tetramethylguanidine.
According to a preferred embodiment of the present process the organic base used is 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5)(DBU).
Preferably the molar ratio between the organic base and the pregnane derivative of formula (I) ranges between 1:1 and 2:1, and more preferably is 1.3:1.
The solvent used in the present isomerisation process is any aprotic polar organic solvent; furthermore, to obtain the advantages described above, also solvents in the non-anhydrous form may be used.
According to a preferred embodiment of the present invention, the reaction solvent used is selected from the group consisting of dimethylformamide, tetrahydrofuran, acetone and acetonitrile.
The process of the invention may be carried out at room temperature, generally at a temperature ranging from 0 to 50xc2x0 C.
According to the present invention, the reaction times range between 3 and 48 hrs. The following examples are conveyed by way of indication, not of limitation, of the present invention.